Retrograde Signalling by Endocannabinoids 375hibition of GABAergic and glutamatergic synaptic transmission in the hippocam-
pus and nucleus accumbens, respectively (Maejima et al. 2001; Varma et al. 2001;
Kim et al. 2002; Ohno-Shosaku et al. 2002). In contrast, both Ca2+-dependent and
Ca2+-independent endocannabinoid-mediated long-term plasticity has been ob-
served. Postsynaptic BAPTA abolishes stimulation-induced LTD of glutamatergic
synaptic transmission in the striatum and nucleus accumbens (Gerdeman et al.
2002; Robbe et al. 2002; see also Huang et al. 2003), but not of GABAergic synaptic
transmission in the hippocampus (Chevaleyre and Castillo 2003).
3.2
Depolarisation and Stimulation/mGluR-Induced Depression:
Distinct Intracellular Cascades and Endocannabinoids?
A major question to be addressed is which endocannabinoids mediate retrograde
endocannabinoid signalling? Both anandamide and 2-AG are potential candidates
as retrograde signallers because their exogenous application produces presynaptic
inhibition,albeitwithreducedpotencyandefficacycomparedtosyntheticagonists
(see Sect. 1.2). The Ca2+-dependent depolarisation-induced short-term retrograde
endocannabinoid signalling is not mediated by postsynaptic G protein-coupled
processes and the PLC/DAG lipase cascade (Kim et al. 2002; Chevaleyre and Castillo
2003). It might be speculated that anandamide mediates depolarisation-induced
short-term depression because anandamide formation/release can be induced by
neuronal activation and Ca2+influx. However, a role for 2-AG cannot be entirely
ruled out because cellular Ca2+influx also promotes its formation.
Stimulation-induced LTD within the hippocampus and nucleus accumbens is
likely to be mediated by activation of group I mGluRs (see Sect. 2.4). Group I
mGluRs are coupled via Gq-proteins/PLC to produce DAG and to increase intra-
cellular Ca2+via IP 3 and ryanodine sensitive stores (Conn and Pin 1997). The
Ca2+-independent endocannabinoid-mediated LTD within the hippocampus is
mediated by the PLC/DAG cascade because it is abolished by PLC and DAG li-
pase inhibitors (Chevaleyre and Castillo 2003). On the other hand, the Ca2+-
dependent endocannabinoid-mediated LTD in the nucleus accumbens is mediated
by the PLC mobilisation of intracellular Ca2+because it is abolished thapsigargin
and ryanodine (Robbe et al. 2002). It might be speculated that 2-AG mediates
stimulation/mGluR-induced depression because 2-AG formation is activated via
thePLCcascade(seeSect.1.1)andhigh-frequencystimulation-inducedhippocam-
pal LTP is associated with an increase in 2-AG, but not anandamide production
(Stella et al. 1997). However, a role for anandamide cannot be entirely ruled out
because neuronal activation, Ca2+influx and G protein-coupled receptor activation
can also trigger anandamide (Piomelli 2003). In addition, striatal LTD is mimicked
by loading the postsynaptic cell with either anandamide, or 2-AG (Gerdeman et
al. 2002; Ronesi et al. 2004).
In summary, the endocannabinoids involved in the types of retrograde endo-
cannabinoid signalling described to date are not fully understood. This will only
be resolved by more fully comparing the intracellular cascades involved in the